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Pentosan Polysulfate: A Novel Therapy for the Mucopolysaccharidoses  [PDF]
Edward H. Schuchman, Yi Ge, Alon Lai, Yury Borisov, Meghan Faillace, Efrat Eliyahu, Xingxuan He, James Iatridis, Helen Vlassara, Gary Striker, Calogera M. Simonaro
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0054459
Abstract: Background Pentosan polysulfate (PPS) is an FDA-approved, oral medication with anti-inflammatory and pro-chondrogenic properties. We have previously shown that animal models of the mucopolysaccharidoses (MPS) exhibit significant inflammatory disease, contributing to cartilage degeneration. Enzyme replacement therapy (ERT) only partly reduced inflammation, and anti-TNF-alpha antibody therapy significantly enhanced clinical and pathological outcomes. Here we describe the use of PPS for the treatment of MPS type VI rats. Methodology/Principal Findings Treatment began during prenatal development and at 1 and 6 months of age. All animals were treated until they were 9 months old. Significant reductions in the serum and tissue levels of several inflammatory markers (e.g., TNF-alpha, MIP-1alpha and RANTES/CCL5) were observed, as was reduced expression of inflammatory markers in cultured articular chondrocytes. ADAMTS-5/aggrecanase-2 levels also were reduced in chondrocytes, consistent with an elevation of serum tissue inhibitor of metalloproteinase 1. Marked improvements in motility and grooming behavior occurred, along with a reduction in eye and nasal secretions and a lessening of the tracheal deformities. MicroCT and radiographic analyses further revealed that the treated MPS skulls were longer and thinner, and that the teeth malocclusions, misalignments and mineral densities were improved. MicroCT analysis of the femurs and vertebrae revealed improvements in trabecular bone mineral densities, number and spacing in a subset of treated MPS animals. Biomechanical assessments of PPS-treated spines showed partially restored torsional behaviors, suggesting increased spinal stability. No improvements were observed in cortical bone or femur length. The positive changes in the PPS-treated MPS VI rats occurred despite glycosaminoglycan accumulation in their tissues. Conclusions Based on these findings we conclude that PPS could be a simple and effective therapy for MPS that might provide significant clinical benefits alone and in combination with other therapies.
Sodium pentosan polysulfate resulted in cartilage improvement in knee osteoarthritis - An open clinical trial-
Kenji Kumagai, Susumu Shirabe, Noriaki Miyata, Masakazu Murata, Atsushi Yamauchi, Yasuhumi Kataoka, Masami Niwa
BMC Pharmacology and Toxicology , 2010, DOI: 10.1186/1472-6904-10-7
Abstract: Twenty patients were assessed clinically at Nagasaki University Hospital. The radiographic indications of OA were grade 1 to 3 using the Kellgren-Lawrence Grading System (K/L grade). Pentosan used in this study was manufactured and supplied in sterile injectable vials (100 mg/ml) by bene GmbH, Munich, Germany. The study was a single-center, open-label trial. Treatment consisted of 6 weekly subcutaneous injections (sc) of pentosan (2 mg/kg). Patients were clinically assessed at entry and 1 to 8, 11, 15, 24 & 52 weeks post treatment. The results were analyzed using one way ANOVA and Dunnett's method.Hydrarthroses were reduced quickly in all cases. The clinical assessments, i.e., knee flexion, pain while walking, pain after climbing up and down stairs, etc, were improved significantly and these clinical improvements continued for almost one year. The dose used in this study affected the blood coagulation test, but was within safe levels. Slightly abnormal findings were noted in serum triglycerides.Pentosan treatment in twenty patients with mild knee OA seemed to provide improvements in clinical assessments and C2C level of cartilage metabolism.UMIN Clinical Trials Registry (UMIN-CTR) UMIN000002790Osteoarthritis (OA) is the most widespread joint disease affecting the elderly population [1]. Non-steroidal anti-inflammatory drugs (NSAIDs), supplements of chondroitin sulfate and/or glycosaminoglycans are prescribed as non-operative treatments. Recently, intraarticular injection of hyaluronic acid (HA) has become a common treatment. Within the last few decades, the concept of disease-modifying osteoarthritis drugs (DMOADs) has been explored as an alternative therapeutic treatment for OA.From the results of previous in vitro and animal model studies, we have proposed that the spectrum of pharmacological activities exhibited by pentosan polysulfate sodium (pentosan) would qualify it as DMOADs. However, there is little human clinical evidence to support this proposition. The a
Dose Responsive Effects of Subcutaneous Pentosan Polysulfate Injection in Mucopolysaccharidosis Type VI Rats and Comparison to Oral Treatment  [PDF]
Michael Frohbergh, Yi Ge, Fanli Meng, Nesrin Karabul, Alexander Solyom, Alon Lai, James Iatridis, Edward H. Schuchman, Calogera M. Simonaro
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0100882
Abstract: Background We previously demonstrated the benefits of daily, oral pentosan polysulfate (PPS) treatment in a rat model of mucopolysaccharidosis (MPS) type VI. Herein we compare these effects to once weekly, subcutaneous (sc) injection. The bioavailability of injected PPS is greater than oral, suggesting better delivery to difficult tissues such as bone and cartilage. Injected PPS also effectively treats osteoarthritis in animals, and has shown success in osteoarthritis patients. Methodology/Principal Findings One-month-old MPS VI rats were given once weekly sc injections of PPS (1, 2 and 4 mg/kg, human equivalent dose (HED)), or daily oral PPS (4 mg/kg HED) for 6 months. Serum inflammatory markers and total glycosaminoglycans (GAGs) were measured, as were several histological, morphological and functional endpoints. Overall, weekly sc PPS injections led to similar or greater therapeutic effects as daily oral administration. Common findings between the two treatment approaches included reduced serum inflammatory markers, improved dentition and skull lengths, reduced tracheal deformities, and improved mobility. Enhanced effects of sc treatment included GAG reduction in urine and tissues, greater endurance on a rotarod, and better improvements in articular cartilage and bone in some dose groups. Optimal therapeutic effects were observed at 2 mg/kg, sc. No drug-related increases in liver enzymes, coagulation factor abnormalities or other adverse effects were identified following 6 months of sc PPS administration. Conclusions Once weekly sc administration of PPS in MPS VI rats led to equal or better therapeutic effects than daily oral administration, including a surprising reduction in urine and tissue GAGs. No adverse effects from sc PPS administration were observed over the 6-month study period.
Pentosan Polysulfate Decreases Myocardial Expression of the Extracellular Matrix Enzyme ADAMTS4 and Improves Cardiac Function In Vivo in Rats Subjected to Pressure Overload by Aortic Banding  [PDF]
Maria Vistnes, Jan Magnus Aronsen, Ida G. Lunde, Ivar Sjaastad, Cathrine R. Carlson, Geir Christensen
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0089621
Abstract: Background We hypothesized that cleavage of the extracellular matrix (ECM) proteoglycans versican and aggrecan by ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) proteases, which contributes to stress-induced ECM-reorganization in atherogenesis and osteoarthritis, also play a role in heart failure development. Objectives The primary objective was to identify alterations in expression of ADAMTS versicanases and aggrecanases during development of heart failure, while evaluation of the effects of in vivo modulation of relevant changes in ADAMTS activity constituted the secondary objective. Methods Myocardial levels of versican, aggrecan, and their ADAMTS cleaving proteases were examined in Wistar rats six weeks after aortic banding (AB), and versican and selected ADAMTS versicanases were further analyzed in neonatal cardiomyocytes (NCM) and cardiac fibroblasts (NFB) after stimulation by inflammatory mediators. Based on the initial findings, ADAMTS4 was selected the most promising therapeutic target. Thus, rats with AB were treated with pentosan polysulfate (PPS), a polysaccharide with known ADAMTS4-inhibitory properties, and effects on versican fragmentation, left ventricular function and geometry were evaluated. Results We discovered that myocardial mRNA and protein levels of ADAMTS1 and -4, and mRNA levels of versican, aggrecan, and ADAMTS8 increased after AB, and TNF-α and IL-1β synergistically increased mRNA of versican and ADAMTS4 in NCM and NFB and secretion of ADAMTS4 from NCM. Furthermore, PPS-treatment improved systolic function, demonstrated by an improved fractional shortening (vehicle 48±3% versus PPS 60±1%, p<0.01) after AB. Following PPS-treatment, we observed an ~80% reduction in myocardial ADAMTS4 mRNA (p = 0.03), and ~50% reduction in the extracellular amount of the p150 versican fragments (p = 0.05), suggesting reduced versicanase activity. Conclusions Our findings suggest that AB induces an increase in myocardial ADAMTS4 versicanase activity, and that PPS-treatment improved systolic function in the pressure-overloaded heart, holding promise as a novel therapeutic agent in heart failure.
Ideal hepatotoxicity model in rats using Carbon Tetrachloride (CCl4)
AJ Alhassan, MJ Sule, SA Aliyu, MD Aliyu
Bayero Journal of Pure and Applied Sciences , 2009,
Abstract: A study to produce ideal Hepatotoxicity rats’ models using varying concentrations of carbon tetrachloride (CCl4) was carried out. A total of seventy five rats were divided into five (5) groups of twenty five (25) rats each; rats in group I are negative control, were not induced with lipid peroxidation. Rats in groups II, III, IV and V were induced with lipid peroxidation and liver damage using, 90, 105 and 120mg/Kg body weight CCl4 respectively. Five (5) rats were removed from each group after 48 hours, 72 hours (3 days) and 144 hours (6 days) of inducement with CCl4 and sacrificed for blood sample collection. Sera obtained were analyzed for alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) activities, and for Malondialdehyde (MDA), total protein (TP) and albumin (ALB) concentrations. After 48hours, rats treated with various concentrations of CCl4 had mean serum activities/ levels of AST, ALT, ALP, MDA, TP and ALB significantly higher (p< 0.05) than normal rats. The control group had 39.5±0.71, 11.5±2.12, 36±7.07U/L, 0.0769 ± 0.015 μM, 43.5±3.54, 19 .00 ± 2.83 g/L respectively. Rats treated with 75mg of CCl4 showed activities/level non significant (p>0.05) increase of serum AST, ALT, ALP, and MDA after 96 hours of CCl4 treatment compared with control group. However, rats treated with 90, 105 and 120mg/kg of CCl4 showed persistently high serum AST, ALT, ALP in U/L, MDA in μM/L, TP and ALB in g/L. even at 144 hours after the treatment. Ideal hepatotoxicity rat model using CCl4 requires a dosage that can cause massive liver damage. Key Words: carbon tetrachloride, hepatotoxicity rats modeling, natural healing.
Jabbar Zoobi,Ali Mohd
International Research Journal of Pharmacy , 2011,
Abstract: In Indian traditional system of medicine, herbal remedies are prescribed for the treatment of various diseases including liver diseases. The present study was aimed to investigate the hepatoprotective activity of the ethanolic extract of Althaea officinalis against Carbon tetrachloride induced hepatotoxicity in rats. Liver function were assessed by the determination of SGPT and SGOT studies. The serum biochemical analysis results suggested that the use of ethanolic extract of Althaea officinalis exhibited significant protective effect from hepatic damage in CCl4 induced hepatotoxicity model.
Hepatoprotective effects of berberine on carbon tetrachloride-induced acute hepatotoxicity in rats
Yibin Feng, Ka-Yu Siu, Xingshen Ye, Ning Wang, Man-Fung Yuen, Chung-Hang Leung, Yao Tong, Seiichi Kobayashi
Chinese Medicine , 2010, DOI: 10.1186/1749-8546-5-33
Abstract: Sprague-Dawley rats aged seven weeks were injected intraperitoneally with 50% CCl4 in olive oil. Berberine was orally administered before or after CCl4 treatment in various groups. Twenty-four hours after CCl4 injection, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, serum and liver superoxide dismutase (SOD) activities were measured. Histological changes of liver were examined with microscopy.Serum ALT and AST activities significantly decreased in a dose-dependent manner in both pre-treatment and post-treatment groups with berberine. Berberine increased the SOD activity in liver. Histological examination showed lowered liver damage in berberine-treated groups.The present study demonstrates that berberine possesses hepatoprotective effects against CCl4-induced hepatotoxicity and that the effects are both preventive and curative. Berberine should have potential for developing a new drug to treat liver toxicity.Liver damage induced by carbon tetrachloride (CCl4) involves biotransformation of free radical derivatives, increased lipid peroxidation and excessive cell death in liver tissue [1,2]. This model of CCl4-induced liver injury has been widely used in new drug development for liver diseases.Berberine is a plant alkaloid present in many medicinal herbs, such as Hydrastis canadensis, Coptidis Rhizoma, Berberis aquifolium, Berberis aristata and Berberis vulgaris [3]. Coptidis Rhizoma (Huanglian), which is rich in berberine, exhibited hepatoprotective effects on CCl4-induced liver injury via scavenging the peroxidative products [4]. Antioxidative effects of Coptidis Rhizoma and its major active ingredient berberine against peroxynitrite-induced kidney damage were demonstrated in vitro and in vivo [5]. Previous studies reported that berberine inhibited inflammation [6] and low-density lipoprotein (LDL) oxidation [7]. Other studies found that berberine was a candidate drug for Alzheimer's disease [8] and cancer [9]. Berberine exhib
Studies on hepatoprotective activity of traditional ayurvedic formulation ‘Vidakana Choornam’ against carbon tetrachloride induced hepatotoxicity in albino rat
Jayarama Reddy, Gnanasekaran D, Ranganathan TV and Vijay D
International Journal of Pharmaceuticals Analysis , 2010,
Abstract: The study was carried out to ascertain the hepatoprotective activity of traditional ayurvedicformulation ‘Vidakana Choornam’ against carbon tetrachloride induced hepatotoxicity in albino rat. Effect ofcarbon tetrachloride and herbal products on liver weights was studied. Bilirubin level in serum, SerumGlutamate Pyruvate Transaminase (GPT) level in serum, Serum Glutamate Oxaloacetate Transaminase(GOT) level in serum and ALP level in serum were estimated in both control treatment. Histopathologicalstudies were also carried out. It was found that there was an increase in liver weight during carbontetrachloride treatment which may be due to accumulation of fat. The results of Vidakana Choornam’treatment against carbon tetrachloride induced hepatotoxicity revealed that there was considerablereduction in Bilirubin level in serum, Serum Glutamate Pyruvate Transaminase (GPT) level in serum, SerumGlutamate Oxaloacetate Transaminase (GOT) level in serum and ALP level in serum. The hepatoprotectiveactivity of this simple formulation was found to be as effective as Liv – 52, infact the activity on decreasingthe serum bilirubin level was much higher when compared to Liv – 52
Hepatoprotective Activity of Ethanolic Extract of the Stems of Anisochilus Carnosus against Carbon Tetrachloride-induced Hepatotoxicity in Rats
P Venkatesh, A Dinakar, N Senthilkumar
International Journal of Health Research , 2010,
Abstract: Purpose: To evaluate the hepatoprotective activity of ethanolic extract of the stems of Anisochilus Carnosus (EEAC) against carbon tetrachloride (CCl4) induced hepatotoxicity in rats. Methods: Hepatotoxicity was induced in albino Wistar rats of either sex by intraperitoneal injection of CCl4 in olive oil (1:1). Two doses of ethanolic extract of Anisochilus Carnosus (200 and 400 mg/kg body weight) were administered to the experimental rats. The hepatoprotective effect of the extract was evaluated by the assay of liver function biochemical parameters like serum glutamate pyruvate transaminase, serum glutamate oxaloacetate transaminase, alkaline phosphatase, total bilirubin and total protein. Results: In ethanolic extract treated animals, the toxic effect of CCl4 was significantly controlled by the plant extract as compared to the normal and the standard drug silymarin treated group. Conclusion: Ethanolic extract of stems of Anisochilus Carnosus possesses significant hepatoprotective activity.
The Effects of Yaji Extract On Liver Enzymes of Carbon Tetrachloride Induced Hepatotoxicity In Adult Wistar Rats  [PDF]
1 Ezejindu D.N
American Journal of Engineering Research , 2013,
Abstract: Effects of yaji extract on liver enzymes of carbon tetrachloride induced hepatotoxicity were studied. Twenty wistar rats weighing between 155-220g were used. They were allocated into four groups of five animals each. Group A animals served as the control and received 0.6ml of distilled water. Group B received 0.5ml of yaji extract, group C received 0.5ml of yaji extract plus 0.3ml of carbon tetrachloride while group D received 0.3ml of carbon tetrachloride. The oral administration lasted for twenty-eight days. Twenty-four hours after the last administration, the animals were weighed and sacrificed using chloroform. The Liver weight were recorded. The evaluation of the liver enzymes (AST, ALP,ALT) were carried out using randox kit method. The mean alkaline phosphatase (ALP), alanine amino transferase (ALT) and aspartate aminotransferase (AST) levels of group D animals were significantly higher than the control.
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